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It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD).To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD.This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (From HCs to iRBD and finally to theOur findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

New findings What is the central question of this study? What is the role of the renal nerves in the development of obesity, hyperlipidemia, and hypertension during the long-term feeding of a moderately high-fat (MHF) diet in male obesity-prone rats? What is the main finding and its importance? The renal nerves play a prominent mediatory role, without influencing the establishment of visceral adiposity and atherogenic hyperlipidemia, in the induction and progression of pressure-natriuresis impairment and hypertension during the developmental period of diet-induced obesity. Abstract Feeding a moderately high-fat (MHF) diet in male Sprague-Dawley rats induced obesity, pressure-natriuresis impairment, and hypertension. This study investigated the role of the renal nerves in the impaired pressure-natriuresis and hypertension caused by feeding a MHF-diet. After collecting baseline data on day-0, 12 rats remained on the low-fat diet (LF-group) while the others were switched onto a MHF-diet and diverged into obesity-resistant (OR) or obesity-prone (OP). After 4-weeks, half of the OR and OP rats underwent bilateral renal denervation (BRD) to generate 4 groups: OR, OR/BRD, OP, and OP/BRD (n = 12). During 10-weeks, body-weight, obesity-index, systolic-pressure and renal excretory function were measured regularly. After 10-weeks, renal excretory responses to acute salt-loading and renal autoregulation were evaluated. The OP and OP/BRD groups had greater increases of body-weight and obesity-index during the dietary period compared to the other groups, which by week-10 their body-weight (425.1 ± 7.2 and 411.9 ± 5.1 g) became considerably larger than the LF-group (358.5 ± 6.2 g). Renal sodium-excretion was reduced by ∼20% at week-4 in the OP and OP/BRD groups, while only the OP-group had lower sodium-excretion at weeks 6-8 and higher systolic-pressure over weeks 5-10 than the other groups and its week-10 systolic-pressure reached 138.1 ± 6.7 versus 123.6 ± 2.7 mmHg of the LF group. The OP-group showed delayed renal excretory responses to salt-loading with rightward and downward shifts in renal autoregulatory curves. Therefore, the renal nerves exert a main mediatory role in the development of pressure-natriuresis impairment and hypertension as obesity is established due to the long-term consumption of the MHF-diet in male OP-rats. This article is protected by copyright. All rights reserved.

Corticosteroids are stress-related hormones that maintain homeostasis. The most effective corticosteroids are corticosterone (CORT) in rodents and cortisol in primates. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1; EC 1.1.1.146), encoded by Hsd11b1, is a key regulator of the local concentration of CORT/cortisol. Hsd11b1 expression in layer 5 of the primary somatosensory cortex has been shown in adult mice. However, its localization in the entire neocortex, especially during development, has not been fully addressed. Here, we established robust and dynamic expression profiles of Hsd11b1 in the developing mouse neocortex. Hsd11b1 was found mostly in pyramidal neurons. By retrograde tracing, we observed that some Hsd11b1-positive cells were projection neurons, indicating that at least some were excitatory. At postnatal day 0 (P0), Hsd11b1 was expressed in the deep layer of the somatosensory cortex. Then, from P3 to P8, the expression area expanded broadly; it was observed in layers 4 and 5, spanning the whole neocortex, including the primary motor cortex (M1) and the primary visual cortex (V1). The positive region gradually narrowed from P14 onwards and was ultimately limited to layer 5 of the somatosensory cortex at P26 and later. Furthermore, we administered CORT to nursing dams to increase the systemic CORT level of their pups. Here, we observed a reduced number of Hsd11b1-positive cells in the neocortex of these pups. Our observation suggests that Hsd11b1 expression in the developing neocortex is affected by systemic CORT levels. It is possible that stress on mothers influences the neocortical development of their children.

Botulinum neurotoxins (BoNTs) are paralytic agents used to treat a variety of conditions in jaw muscles. Although their effect is considered temporary, there are reports of persistent functional changes. Using rabbits that received BoNT injection in one masseter muscle, the recovery of neuromuscular connection was investigated using nerve stimulation to evoke an electromyographic (EMG) response, and the recovery of muscle fibers was investigated using histological morphometry and bromodeoxyuridine (BrdU) immunohistochemistry. One month after treatment, evoked EMG was greatly reduced in both amplitude and duration, indicating that little reinnervation had taken place. Muscle fibers were atrophied and collagenous tissue was increased. Three months after treatment, evoked EMG duration was normal, indicating that at least some neuromuscular junctions were functional. Histologically, some muscle fibers were hypertrophied, some were still atrophied, and some appeared to have died. Fibrosis was still apparent amid slight increases in dividing cells and regenerating fibers. The histological effects of BoNT were evident although attenuated at a distance of about 1 cm from the injection level, but no regional differences could be discerned for the evoked EMGs. In conclusion, there were persistent muscular deficits seen 3 months after BoNT treatment that may have been caused by the failure of some affected muscle fibers to become reinnervated.

The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting neurons and interneurons. This system regulates many functions of human behavior such as cognition, locomotion, and sleep. In Parkinson's disease (PD), disruption of central cholinergic transmission has been associated with cognitive decline, gait problems, freezing of gait (FOG), falls, REM sleep behavior disorder (RBD), neuropsychiatric manifestations, and olfactory dysfunction. Neuropathological and neuroimaging evidence suggests that basal forebrain pathology occurs simultaneously with nigrostriatal denervation, whereas pathology in the pontine nuclei may occur before the onset of motor symptoms. These studies have also detailed the clinical implications of cholinergic dysfunction in PD. Degeneration of basal forebrain nuclei and consequential cortical cholinergic denervation are associated with and may predict the subsequent development of cognitive decline and neuropsychiatric symptoms. Gait problems, FOG, and falls are associated with a complex dysfunction of both pontine and basal forebrain nuclei. Olfactory impairment is associated with cholinergic denervation of the limbic archicortex, specifically hippocampus and amygdala. Available evidence suggests that cholinergic dysfunction, alongside failure of the dopaminergic and other neurotransmitters systems, contributes to the generation of a specific set of clinical manifestations. Therefore, a "cholinergic phenotype" can be identified in people presenting with cognitive decline, falls, and RBD. In this review, we will summarize the organization of the central cholinergic system and the clinical correlates of cholinergic dysfunction in PD.

INTRODUCTION/AIMS Obesity is a factor contributing to suboptimal improvement of motor function in peripheral nerve disorders. In this study we aimed to evaluate the skeletal muscles during denervation and reinnervation after nerve crush injury in leptin-deficient (ob/ob) mice. METHODS Experiments were performed on the skeletal muscles of the hindlimbs in 20 male ob/ob mice and controls. Characteristics of the gastrocnemius muscles were evaluated by histological analysis, immunohistological analysis, and Sircol-collagen assay after measurement of body weight and wet weight of the skeletal muscles, and by walking track analysis. The sciatic nerve was denervated by crushing with smooth forceps and reinnervation was evaluated. RESULTS Gastrocnemius wet weight was significantly lower in the ob/ob mice than in the control mice. A smaller cross-sectional area of type II fibers and increase of type I fiber grouping of the skeletal muscles was demonstrated in the ob/ob mice. After nerve injury, motor function recovery was equal between the groups but the cross-sectional area of type II fibers was significantly smaller in the ob/ob mice than in control mice at 4 weeks. The denervated muscles showed an increase in collagen deposition in the interstitial space; predominant in the ob/ob mice after nerve injury. DISCUSSION The results of this study suggest that fibrosis in the skeletal muscle of obese patients after nerve injury is prominent, which may impair improvement of muscle function after treatment of peripheral nerve disorders.

Background Asymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression. Objectives The objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naive PD. Methods From the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data. Results At baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time. Conclusions These findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with an extremely heterogeneous clinical and genetic phenotype. In our efforts to find therapies for ALS, the scientific community has developed a plethora of mouse models, each with their own benefits and drawbacks. The peripheral nervous system, specifically the neuromuscular junction (NMJ), is known to be affected in ALS patients and shows marked dysfunction across mouse models. Evidence of pathology at the NMJ includes denervated NMJs, changes in endplate size and loss of terminal Schwann cells. This review compares the temporal disease progression with severity of disease at the NMJ in mouse models with the most commonly mutated genes in ALS patients (SOD1, C9ORF72, TARDBP and FUS). Despite variability, early NMJ dysfunction seems to be a common factor in models with SOD1, TARDBP and FUS mutations, while C9ORF72 models do not appear to follow the same pattern of pathology. Further work into determining the timing of NMJ pathology, particularly in newer ALS mouse models, will confirm its pivotal role in ALS pathogenesis and therefore highlight the NMJ as a potential therapeutic target.

INTRODUCTION Renal sympathetic denervation (RSDN) is an alternate management approach for refractory ventricular arrhythmias (VAs). We aimed to perform a systematic review of clinical outcomes on the impact of RSDN on refractory VA patients. METHODS A systematic search without language restriction, using PubMed, EMBASE, SCOPUS, Google Scholar, and ClinicalTrials.gov from inception to August 18, 2020, was performed for the studies that reported outcomes in patients who underwent RSDN for VA. The outcomes studied were-(1) recurrent VA; and (2) all-cause mortality. RESULTS Five studies (from 2014 to 2018) with a total of 51 VA patients met study inclusion criteria. The mean age was 61.92 ± 11.76 years, and 78.4% were men. The pooled incidence of short-term (3 months or less) and long-term (more than 3 months) VA recurrence was 63.85% (95% CI 16.75 to 99.32) and 10.52% (95% CI 0.14 to 28.75), respectively. When stratified by the number of VA episodes, there was a significant reduction in mean VA episodes (SMD -3.79, 95% CI -6.59 to -0.98, p

Cardiac innervation density generally reflects the levels of nerve growth factor (NGF) produced by the heart—changes in NGF expression within the heart and vasculature contribute to neuronal remodelling (e.g. sympathetic hyperinnervation or denervation). Its synthesis and release are altered under different pathological conditions. Although NGF is well known for its survival effects on neurons, it is clear that these effects are more wide ranging. Recent studies reported both in vitro and in vivo evidence for beneficial actions of NGF on cardiomyocytes in normal and pathological hearts, including prosurvival and antiapoptotic effects. NGF also plays an important role in the crosstalk between the nervous and cardiovascular systems. It was the first neurotrophin to be implicated in postnatal angiogenesis and vasculogenesis by autocrine and paracrine mechanisms. In connection with these unique cardiovascular properties of NGF, we have provided comprehensive insight into its function and potential effect of NGF underlying heart sustainable/failure conditions. This review aims to summarize the recent data on the effects of NGF on various cardiovascular neuronal and non‐neuronal functions. Understanding these mechanisms with respect to the diversity of NGF functions may be crucial for developing novel therapeutic strategies, including NGF action mechanism‐guided therapies.

Reduced nerve growth factor (NGF) is associated with cardiac sympathetic nerve denervation in heart failure (HF) which is characterized by increased oxidative stress. Apocynin is considered an antioxidant agent which inhibits NADPH oxidase activity and improves reactive oxygen species scavenging. However, it is unclear whether apocynin prevents reduced myocardial NGF, leading to improvement of cardiac function in HF. In this study, we tested the hypothesis that apocynin prevents reduced myocardial NGF, contributing to amelioration of myocardial apoptosis and failure. Rabbits with myocardial infarction (MI) or sham operation were randomly assigned to receive apocynin or placebo for 4 weeks. MI rabbits exhibited left ventricular (LV) dysfunction, and elevation in oxidative stress, as evidenced by a decreased reduced-to-oxidized glutathione ratio and an increased 4-hydroxynonenal expression, and reduction in NGF and NGF receptor tyrosine kinase A (TrKA) expression in the remote non-infarcted myocardium. Apocynin treatment ameliorated LV dysfunction, reduced oxidative stress, prevented decreases in NGF and TrKA expression and reduced cardiomyocyte apoptosis after MI. In cultured H9C2 cardiomyocytes, hypoxia or hydrogen peroxide decreased NGF expression, and apocynin normalized hypoxia-induced reduction of NGF. Recombinant NGF attenuated hypoxia-induced apoptosis. Apocynin prevented hypoxia-induced apoptosis, and the suppressive effect of apocynin on apoptosis was abolished by NGF receptor TrKA inhibitor K252a. We concluded that apocynin prevented reduced myocardial NGF, leading to attenuation of cardiomyocyte apoptosis and LV remodelling and dysfunction in HF after MI. These findings suggest that strategies to prevent NGF reduction by inhibition of oxidative stress may be of value in amelioration of LV dysfunction in HF.

Data suggest that renal denervation (RDN) in treatment-resistant hypertension (TRHT) is safe in terms of renal function. However, most studies report kidney function as creatinine-based estimated glomerular filtration rate (eGFR), which may be biased by non-renal factors. Damage markers other than albuminuria have never been evaluated after RDN. In this non-randomized RDN trial, we studied changes in kidney function, assessed as measured GFR (mGFR) and various GFR estimates, six months and two years after RDN. We also examined changes in albuminuria and a biomarker of tubular dysfunction. Adult non-diabetic patients with TRHT and eGFR ≥45 ml/min/1.73 m2 were recruited from hypertension clinics. Before bilateral RDN, mGFR was measured by iohexol clearance. We estimated eGFR from serum creatinine and cystatin C (eGFRcrea, eGFRcys, and eGFRcreacys), and albumin-creatinine ratio (ACR) and N-acetyl-β-D-glucosaminidase (NAG)-creatinine ratio (NAG-CR) were measured in spot urines. All measurements were repeated after six and twenty-four months. Twenty patients, mean age 54 (±9) years and baseline mGFR 83 (±20) ml/min/1.73 m2 underwent RDN. After six months, mGFR fell, eGFRcrea remained unchanged, whereas eGFRcys and eGFRcreacys increased. At 2 years’ follow-up, eGFRcreacys was significantly lower than at baseline. mGFR was 78 (±28) ml/min/1.73 m2. Change in ambulatory systolic BP predicted change in eGFRcrea. Urinary NAG-CR, but not ACR, increased during follow-up. Different GFR assessments gave diverging results after RDN. Therefore, care should be taken to method when evaluating kidney function after RDN. Increases in a tubular dysfunction biomarker suggest that kidney damage may occur. Long-term renal follow-up is needed after RDN.

Objectives The present study was a prospective, single-center, single-arm study to investigate the efficacy of transcatheter pulmonary artery denervation (TPADN) in patients with combined postcapillary and precapillary PH (Cpc-PH) associated with left heart failure with reduced ejection fraction (HF-rEF). Background Pulmonary hypertension (PH) in patients with left ventricular systolic dysfunction has a negative impact on outcome. Methods The combination of pulmonary artery systolic pressure (PAPs) ≥60 mmHg, transpulmonary pressure gradient (TPG) ≥12 mmHg, nonreversible mean PAP, and pulmonary vascular resistance (PVR) ≥3.5 Wood Units was considered as too high risk for heart transplantation (HTx). The clinical efficacy endpoint was an improvement in 6-min walking test and the hemodynamic endpoints were changes in PAPs, PVR, and TPG between baseline and 6 months. Circumferential radiofrequency applications were delivered around distal main, left and right pulmonary arteries. At each ablation point temperature was 45°C and energy 10 W. Results TPADN was performed in 10 patients. At 6-month in 5 patients we observed reduction in PAP, PVR, TPG, and DPG and then 1 had successful HTx, 2 are on HTx waiting list, 2 received LVADs, 2 patients did not improve, and 3 patients died. Conclusions TPADN may be beneficial in selected patients with HF-rEF and Cpc-PH.

Objective The effect of patellar denervation with electrocautery (PD) on anterior knee pain (AKP) after total knee arthroplasty (TKA) is still debated. The aim of this meta-analysis was to evaluate the current evidence regarding the use of PD in TKA without patellar resurfacing. Methods A computerized search of published studies was performed in the PubMed, Embase and Cochrane Library databases in December 2019. Eligible studies were randomized controlled trials (RCTs) comparing clinical outcomes of the PD group and the non-PD group. Subgroup analyses were carried out according to the follow-up time (3, 12 months, and over 12 months) to evaluate whether the clinical effect of PD changed with time. Results Ten RCTs were included in this meta-analysis. Pooled results showed a lower rate of AKP (Risk Ratio [RR] = 0.70; 95% confidence interval [CI], 0.50 to 0.97; P = 0.03) and a reduction in visual analogue scale (VAS) for AKP (mean difference, -0.37; 95% CI, -0.69 to -0.05; P = 0.02) in the PD group when compared to the non-PD group. Subgroup analyses found the differences in AKP incidence and VAS for AKP were significant at 3- and 12-month follow-up but not after 12-month follow-up. No significant difference was observed in functional scores between the two groups. No specific complication directly or indirectly related to PD was found. Conclusion PD can decrease the incidence and severity of AKP within 12 months after TKA, but the effect cannot be maintained after 12-month follow-up. Without significant associated complication and reoperation, the use of PD is still recommended in TKA without patellar resurfacing.

BACKGROUND: Prolonged critically ill patients frequently develop debilitating muscle weakness that can affect both peripheral nerves and skeletal muscle. In-depth knowledge on the temporal contribution of neural and muscular components to muscle weakness is currently incomplete. METHODS: We used a fluid-resuscitated, antibiotic-treated, parenterally fed murine model of prolonged (5 days) sepsis-induced muscle weakness (caecal ligation and puncture; n = 148). Electromyography (EMG) measurements were performed in two nerve-muscle complexes, combined with histological analysis of neuromuscular junction denervation, axonal degeneration, and demyelination. In situ muscle force measurements distinguished neural from muscular contribution to reduced muscle force generation. In myofibres, imaging and biomechanics were combined to evaluate myofibrillar contractile calcium sensitivity, sarcomere organization, and fibre structural properties. Myosin and actin protein content and titin gene expression were measured on the whole muscle. RESULTS: Five days of sepsis resulted in increased EMG latency (P = 0.006) and decreased EMG amplitude (P

Background Ganglionated plexuses (GPs) are implicated in atrial fibrillation (AF). Endocardial high‐frequency stimulation (HFS) delivered within the local atrial refractory period can trigger ectopy and AF from specific GP sites (ET‐GP). The aim of this study was to understand the role of ET‐GP ablation in the treatment of AF. Methods Patients with paroxysmal AF indicated for ablation were recruited. HFS mapping was performed globally around the left atrium to identify ET‐GP. ET‐GP was defined as atrial ectopy or atrial arrhythmia triggered by HFS. All ET‐GP were ablated, and PVs were left electrically connected. Outcomes were compared with a control group receiving pulmonary vein isolation (PVI). Patients were followed‐up for 12 months with multiple 48‐h Holter ECGs. Primary endpoint was ≥30 s AF/atrial tachycardia in ECGs. Results In total, 67 patients were recruited and randomized to ET‐GP ablation (n = 39) or PVI (n = 28). In the ET‐GP ablation group, 103 ± 28 HFS sites were tested per patient, identifying 21 ± 10 (20%) GPs. ET‐GP ablation used 23.3 ± 4.1 kWs total radiofrequency (RF) energy per patient, compared with 55.7 ± 22.7 kWs in PVI (p =

Background Diagnosing cervical radiculopathy (CR) can be difficult because of symptomatic overlap with peripheral neuropathies. In this retrospective observational study, we aimed to determine whether short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) sequences are useful for detecting signs of denervation in the multifidus muscles in patients with CR. Methods We analyzed the data of 18 patients with CR who developed arm weakness within 1 year. We also included 10 patients with sensorimotor symptoms involving the upper extremities who did not have intervertebral foraminal stenosis on MRI as controls. For each patient with CR, the signal intensity (SI) of the affected multifidus muscles was measured and compared to that on the contralateral side (signal intensity ratio: SIR). Results Control patients without CR did not exhibit STIR signal abnormalities in the multifidus muscles. Most of the 18 patients with CR were male (83.3%), and the mean age was 59.4 years. Thirteen of 18 CR patients (72.2%) were determined to have STIR signal abnormalities by a radiologist. The mean SIR in the 13 patients with increased SI was significantly higher than that in the five patients without signal abnormalities (1.23 vs 0.97, P = .004), supporting the radiologist's diagnosis. The distribution of signal abnormalities closely followed those identified via clinical and electrophysiological tests, especially severe weakness (P = .044). Conclusions Denervation edema of the multifidus muscles can be detected in CR and correlates with clinical/electrophysiological tests and weakness severity, which may aid in CR diagnostics.

Objective To report the outcome of horses used in western performance disciplines after deep branch lateral plantar neurectomy/fasciotomy surgery for hind limb proximal suspensory desmopathy (PSD). Study design Retrospective analysis. Sample population Twenty-one client-owned horses. Methods Medical records were reviewed (2009-2019) for horses involved in western performance disciplines that had been treated with deep branch lateral plantar neurectomy and plantar fasciotomy for lameness due to hind limb PSD. Follow-up was obtained by reexamination and/or verbal interviews with owners >2 years postoperatively. Results Sixteen quarter horses and five paints were used for western pleasure (14/21), barrel racing (2/21), cutting (1/21), steer wrestling (1/21), working cow horse (1/21), team roping (1/21) and reining (1/21). A median duration of 8 months was required before horses were able to resume training or athletic work. Nine horses were able to return to a similar or higher level of athletic use, nine horses returned to a lower level of athletic performance, and three horses could not return to intended function. Owner satisfaction with outcome after the procedure was high (16/21), average (3/21), and low (2/21). Conclusion Deep branch lateral plantar neurectomy and plantar fasciotomy allowed most horses to resume some athletic function as western performance horses. Clinical significance These results provide evidence of potential outcomes when considering surgical treatment of hind limb PSD in western performance horses.

Alternative splicing (AS) presents a key posttranscriptional regulatory mechanism associated with numerous physiological processes. However, little is known about its role in skeletal muscle atrophy. In this study, we used a rat model of denervated skeletal muscle atrophy and performed RNA-sequencing to analyze transcriptome profiling of tibialis anterior muscle at multiple time points following denervation. We found that AS is a novel mechanism involving muscle atrophy, which is independent changes at the transcript level. Bioinformatics analysis further revealed that AS transitions are associated with the appearance of the atrophic phenotype. Moreover, we found that the inclusion of multiple highly conserved exons of Obscn markedly increased at 3 days after denervation. In addition, we confirmed that this newly transcript inhibited C2C12 cell proliferation and exacerbated myotube atrophy. Finally, our study revealed that a large number of RNA-binding proteins were upregulated when the atrophy phenotype appeared. Our data emphasize the importance of AS in this process.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of systematic administration of bisphosphonates (BPs). Sensory innervation is crucial for bone healing. We established inferior alveolar nerve injury (IANI) and inferior alveolar nerve transection (IANT) models characterized by disorganized periosteum, increased osteoclasts, and unbalanced neuropeptide expression. Zoledronate injection disrupted neuropeptide expression in the IANI and IANT models by decreasing calcitonin gene-related peptide (CGRP) and increasing substance P (SP); associated with this, BRONJ prevalence was significantly higher in the IANT model, followed by the IANI model and the sham control. CGRP treatment significantly reduced BRONJ occurrence, whereas SP administration had the opposite effect. In vitro, RAW 264.7 cells were treated with BPs and then CGRP and/or SP to study changes in zoledronate toxicity; combined application of CGRP and SP decreased zoledronate toxicity, whereas CGRP or SP applied alone showed no effects. These results demonstrate that sensory denervation facilitates the occurrence of BRONJ and that CGRP used therapeutically may prevent BRONJ progression, provided that SP is also present. Further studies are necessary to determine the optimal ratio of CGRP to SP for promoting bone healing and to uncover the mechanism by which CGRP and SP cooperate.

Background Sarcopenia, or age‐dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co‐morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle‐wasting conditions. Interventions that can adjust neurotransmitter release to changing physiological demands depend on understanding how the SNS affects neuromuscular transmission, muscle motor innervation, and muscle mass. Methods We examined age‐dependent expression of the heart and neural crest derivative 2 (Hand2), a critical transcription factor for SN maintenance, and we tested the possibility that inducing its expression exclusively in sympathetic neurons (SN) will prevent (i) motor denervation, (ii) impaired neuromuscular junction (NMJ) transmission, and (iii) loss of muscle mass and function in old mice. To test this hypothesis, we delivered a viral vector carrying Hand2 expression or an empty vector exclusively in SNs by vein injection in 16‐month‐old C57BL/6 mice that were sacrificed 6 months later. Techniques include RNA‐sequencing, real‐time PCR, genomic DNA methylation, viral vector construct, tissue immunohistochemistry, immunoblot, confocal microscopy, electrophysiology, and in vivo mouse physical performance. Results Hand2 expression declines throughout life, but inducing its expression increased (i) the number and size of SNs, (ii) muscle sympathetic innervation, (iii) muscle weight and force and whole‐body strength, (iv) myofiber size but not muscle fibre‐type composition, (v) NMJ transmission and nerve‐evoked muscle force, and (vi) motor innervation in old mice. Additionally, the SN controls a set of genes to reduce inflammation and to promote transcription factor activity, cell signalling, and synapse in the skeletal muscle. Hand2 DNA methylation may contribute, at least partially, to gene silencing. Conclusions Selective expression of Hand2 in the mouse SNs from middle age through old age increases muscle mass and force by (i) regulating skeletal muscle sympathetic and motor innervation; (ii) improving acetylcholine receptor stability and NMJ transmission; (iii) preventing inflammation and myofibrillar protein degradation; (iv) increasing autophagy; and (v) probably enhancing protein synthesis.

OBJECTIVES/HYPOTHESIS Although vidian neurectomy (VN) is associated with decreased lacrimation, its impact on dry eye quality-of-life is not well-defined. Endoscopic endonasal transpterygoid approaches (EETA) may require vidian nerve sacrifice. STUDY DESIGN A prospective cohort trial. METHODS A prospective trial evaluating VN during EETA on lacrimation by phenol red thread testing and dry eye severity by the five-item Dry Eye Questionnaire (DEQ-5) was performed. Preservation of the contralateral vidian nerve allowed comparison between the eye subjected to VN and the control eye postoperatively. RESULTS Twenty-one subjects were enrolled with no preoperative difference in lacrimation between eyes (P = .617) and overall mild dry eye severity. Although the control eye had no difference in lacrimation pre- and postoperatively, decreased tearing was noted in the VN eye at 1 month (20.8 mm vs. 15.8 mm, P = .015) and at 3 months (23.2 mm vs. 15.8 mm, P = .0051) postoperatively. Overall, no difference was noted in the DEQ-5 score for dry eye severity between the pre- and postoperative measures. However, six patients were noted to have moderate to severe dry eye severity postoperatively and five of these six had decreased lacrimation (

The total motor neuron (MN) somato-dendritic surface area is correlated with motor unit type. MNs with smaller surface areas innervate slow (S) and fast fatigue-resistant (FR) motor units, while MNs with larger surface areas innervate fast fatigue-intermediate (FInt) and fast fatigable (FF) motor units. Differences in MN surface area (equivalent to membrane capacitance) underpin the intrinsic excitability of MNs and are consistent with the orderly recruitment of motor units (S > FR > FInt > FF) via the Size Principle. In amyotrophic lateral sclerosis (ALS), large MNs controlling FInt and FF motor units exhibit earlier denervation and death, compared to smaller and more resilient MNs of type S and FR motor units that are spared until late in ALS. Abnormal dendritic morphologies in MNs precede neuronal death in human ALS and in rodent models. We employed Golgi-Cox methods to investigate somal size-dependent changes in the dendritic morphology of hypoglossal MNs in wildtype and SOD1 mice (a model of ALS), at postnatal (P) day ~30 (pre-symptomatic), ~P60 (onset), and ~P120 (mid-disease) stages. In wildtype hypoglossal MNs, increased MN somal size correlated with increased dendritic length and spines in a linear fashion. By contrast, in SOD1 mice, significant deviations from this linear correlation were restricted to the larger vulnerable MNs at pre-symptomatic (maladaptive) and mid-disease (degenerative) stages. These findings are consistent with excitability changes observed in ALS patients and in rodent models. Our results suggest that intrinsic or synaptic increases in MN excitability are likely to contribute to ALS pathogenesis, not compensate for it.

Objective The aim of the present study was to evaluate the effect of patellar denervation (PD) in preventing anterior knee pain (AKP) and improving knee function after total knee arthroplasty (TKA) without patellar resurfacing, and to help surgeons decide whether or not to use PD in TKA. Methods The electronic databases of Pubmed, Embase, Cochrane, Web of Science, and Scopus were searched for all randomized controlled trials (RCT) comparing the outcomes of PD and no patellar denervation (NPD) in TKA without patellar resurfacing. Primary outcomes were incidence of AKP, visual analogue scale for pain (VAS), and patellar score (PS). Secondary outcomes were Knee Society Score (KSS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Oxford Knee Score (OKS), knee range of motion (ROM), and complications. Results A total of nine RCT met the inclusion criteria. On meta‐analysis, PD significantly reduced the incidence of AKP (odds ratio 0.49; 95% confidence interval [CI] 0.26 to 0.92), reduced the VAS (weighted mean difference [WMD] −0.57; 95% CI −1.02 to −0.11), and improved the WOMAC (WMD −4.63; 95% CI −6.49 to −2.77) and the ROM (WMD 9.60; 95% CI 0.39 to 18.81) during the follow‐up within 12 months. In addition, PD improved the PS (WMD 1.01; 95% CI 0.65 to 1.38), KSS (WMD 1.12; 95% CI 0.10 to 2.14), and the WOMAC (WMD −1.41; 95% CI −2.74 to −0.08) during the follow‐up after 12 months. Conclusion Patellar denervation could significantly reduce the VAS and the incidence of AKP in the early stages after TKA as well as improve the clinical outcomes in terms of the PS, the WOMAC, the KSS, and the ROM. This study demonstrates that PD is a safe and recommendable technique that could be routinely performed in TKA., To evaluate the effect of PD in preventing AKP and improving knee function after TKA without patellar resurfacing and to help surgeons decide whether or not to use PD in TKA. The electronic databases of Pubmed, Embase, Cochrane, Web of Science and Scopus were searched for all randomized controlled trials (RCT) comparing the outcomes of PD and no patellar denervation (NPD) in TKA without patellar resurfacing. PD could significantly reduce the VAS and the incidence of AKP in the early stages after TKA, and improve the clinical outcomes in terms of the PS, the WOMAC, the KSS, and the ROM. This study demonstrates that PD is a safe and recommendable technique that could be routinely performed in TKA.

Background Nerves are key factors in prostate cancer (PCa) progression. Here, we propose that neuropeptide Y (NPY) nerves are key regulators of cancer–nerve interaction. Methods We used in vitro models for NPY inhibition studies and subsequent metabolomics, apoptotic and migration assays, and nuclear transcription factor‐κB (NF‐κB) translocation studies. Human naïve and radiated PCa tissues were used for NPY nerve density biomarker studies. Tissues derived from a Botox denervation clinical trial were used to corroborate metabolomic changes in humans. Results Cancer cells increase NPY positive nerves in vitro and in preneoplastic human tissues. NPY‐specific inhibition resulted in increased cancer apoptosis, decreased motility, and energetic metabolic pathway changes. A comparison of metabolomic response in NPY‐inhibited cells with the transcriptome response in human PCa patients treated with Botox showed shared 13 pathways, including the tricarboxylic acid cycle. We identified that NF‐κB is a potential NPY downstream mediator. Using in vitro models and tissues derived from a previous human chemical denervation study, we show that Botox specifically, but not exclusively, inhibits NPY in cancer. Quantification of NPY nerves is independently predictive of PCa‐specific death. Finally, NPY nerves might be involved in radiation therapy (RT) resistance, as radiation‐induced apoptosis is reduced when PCa cells are cocultured with dorsal root ganglia/nerves and NPY positive nerves are increased in prostates of patients that failed RT. Conclusion These data suggest that targeting the NPY neural microenvironment may represent a therapeutic approach for the treatment of PCa and resistance through the regulation of multiple oncogenic mechanisms.

OBJECTIVE Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using 11 C-methylreboxetine (11 C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using 18 F-dopamine (18 F-DA) to assess intraneuronal vesicular storage in the same subjects. METHODS Seven comprehensively tested PAF patients and 11 controls underwent 11 C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and 18 F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. RESULTS In the PAF group septal 11 C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of 11 C-MRB, the PAF group had a 41.1% mean decrease in myocardial 11 C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of 18 F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p

Background We aimed to examine the influence of different speeds of stretching on denervation-induced skeletal muscle fibrosis. Methods Stretching was passively applied to rat plantaris muscle denervated by sciatic nerve excision in three different cycles of 0.5, 3, or 12 cycles/min, for 20 min/d for 2 weeks. Results Gene analysis results showed greater expression of fibrosis-related factors with fast stretching compared with non-stretched muscle. Laser Doppler blood flow analysis indicated reduced intramuscular blood flow during stretching. Histological analysis demonstrated fibrotic area decreases in 12 cycles/min stretched muscle compared with non-stretched muscle. Conclusions Slower stretching induced greater mRNA expression of collagen and fibroblasts and greater decrement of blood flow. Histologically, faster stretching suppressed fibrosis. These results suggest that fast repetitive stretching of denervated muscle might suppress processes of muscle fibrosis.

Adipose tissue plays an important role in metabolic homeostasis and its prominent role as endocrine organ is now well recognized. Adipose tissue is controlled via the sympathetic nervous system (SNS). New viral, molecular‐genetic tools will soon allow a more detailed study of adipose tissue innervation in metabolic function, yet, the precise anatomical extent of preganglionic and postganglionic inputs to the inguinal white adipose tissue (iWAT) is limited. Furthermore, several viral, molecular‐genetic tools will require the use of cre/loxP mouse models, while the available studies on sympathetic iWAT innervation were established in larger species. In this study, we generated a detailed map for the sympathetic innervation of iWAT in male and female mice. We adapted iDISCO tissue clearing to process large, whole‐body specimens for an unprecedented view of the natural abdominal SNS. Combined with pseudorabies virus retrograde tracing from the iWAT, we defined the preganglionic and postganglionic sympathetic input to iWAT. We used fluorescence‐guided anatomical dissections of sympathetic nerves in reporter mice to further clarify that postganglionic axons connect to iWAT via lateral cutaneous rami (dorsolumbar iWAT portion) and the lumbar plexus (inguinal iWAT portion). Importantly, these rami carry axons that branch to iWAT, as well as axons that travel further to innervate the skin and vasculature, and their functional impact will require consideration in denervation studies. Our study may serve as a comprehensive map for future experiments that employ virally driven neuromodulation techniques to predict anatomy‐based viral labeling., Preganglionic and postganglionic sympathetic inguinal white adipose tissue (iWAT) inputs are anatomically distinct from interscapular brown adipose tissue.Dorsolumbar and inguinal iWAT portions are innervated by anatomically distinct sympathetic nerves.Sympathetic postganglionic iWAT innervation reaches its target organ via lateral cutaneous rami of intercostal nerves T11–L1 and anterior cutaneous femoral nerve (as part of the lumbar plexus, L1)White adipocytes are sparsely innervated (sparse varicosities), while brown adipocytes (beige islands) show dense innervation (dense varicosities) in iWAT.

Previous studies describing renal denervation (RDN) from the intima of the renal artery for the treatment of resistant hypertension have reported variable efficacies, and RDN triggers renal intimal injury and atherosclerosis. This study aimed to evaluate the efficacy and safety of RDN from the adventitia of renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone-producing adenoma (APA). A total of 60 consecutive patients with resistant hypertension caused by unilateral APA were enrolled in this study. Patients were randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n = 30) or adrenalectomy alone (control group, n = 30) and were followed up for 12 months. The primary efficacy end point was the change in 24-hours mean ambulatory systolic blood pressure (SBP) from baseline to 12 months. At the 12-month follow-up, the mean reduction of 24-hours average SBP and office SBP in the RDN group was 20.7 ± 15.2 and 37.1 ± 26.0 mm Hg, respectively, which was significantly higher than the mean reduction of 24-hours average SBP (11.9 ± 11.1 mm Hg, P = .017) and the office SBP (25.9 ± 16.8 mm Hg, P = .035) in the control group. Serum potassium levels returned to normal 12 months post-procedure. Patients in the RDN group had higher proportion of cured clinical and biochemical outcomes than those in the control group (35.7% vs 17.9% in clinical outcome; 96.4% vs 89.3% in biochemical outcome, respectively). There were no procedural-, device-, or treatment-related safety events during the 12-month follow-up period between the groups. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy is more effective than adrenalectomy alone for treating resistant hypertension caused by unilateral APA.